Field of the Invention and Description of the Prior Art
This invention relates to improved forms of medicine, more particularly to soft gelatin capsules containing polyethylene glycol which distinguish themselves by an exceptionally high physical stability and durability.
After a method for the production of soft gelatin capsules had been found in the thirties by which a capsule can be produced and filled in a single operation, gelatin capsules, and in particular soft gelatin capsules, gained more and more importance as a form of medicine. They present a number of advantages over other forms of administration. They are, for instance, odorless and tasteless, easy to swallow, and their swelling properties and solubility in water ensure that the active substances are easily released in the stomach. There are quite a number of active substances which because of their sensitivity to oxidation and light, their thermal instability, or their hygroscopicity cannot be processed into other forms of medicines, but which can be enclosed in capsules without their efficiency being impaired.
Soft gelatin capsules are predominantly employed for enclosing liquids, more particularly oily solutions, suspensions or emulsions. Filling materials normally used are vegetable, animal or mineral oils, liquid hydrocarbons, volatile oils and polyethylene glycols. To improve the consistency, fats or waxes are used or added.
As compared with the other possible filling materials for soft gelatin capsules, polyethylene glycols offer a number of particularities. Contrary to oily liquids, liquid polyethylene glycols can be mixed with water without limitation, and the solid polyethylene glycols are also well soluble in water. Since on the other hand polyethylene glycols are at the same time capable of solving many active substances which themselves are not or only difficulty soluble in water, the use of polyethylene glycols enables such active substances to be released in a particularly favorable manner. Active substances which are difficulty soluble in water and which are dissolved or suspended in polyethylene glycols and then filled into soft gelatin capsules, distinguish themselves in many cases by an exceptionally high bio-availability of the active substances. In Br. J. Clin. Pharmac. (1977), 4, pages 209 to 211, for instance, it has been reported that an especially good bio-availability of digoxin is obtained when the active substance is administered in the form of a polyethylene glycol solution enclosed in a soft gelatin capsule.
In spite of these, mainly bio-pharmaceutical, advantages of soft gelatin capsules the fillings of which contain polyethylene glycols, very considerable difficulties are encountered in the production of physically stable and durable capsules.
Polyethylene glycol has a high affinity to both the material of the gelatin capsule and the softeners used in the shell. The softener normally used for gelatin capsules containing the usual filling materials is in the first line glycerol, but sorbitol and, to a limited degree, polyethylene glycols themselves have also been known as softeners (compare Czetach-Lindenwald and Fahrig, Medicine Capsules, Aulendorf, 1962, pages 26/27, or R. Voight, Manual of Pharmaceutical Technology, 3rd edition, 1979, page 244). It has been generally assumed that the higher hygroscopicity of glycerol renders it more efficient as a softener than sorbitol, and accordingly glycerol is employed in most cases (compare also German Patent Specification No. 22 09 526). However, in most of the cases, the hardness and flexibility of the shells of the capsules start to change shortly after the production of such capsules, due to the reciprocal effects between the fillings, which contain polyethylene glycols, and the soft gelatin capsules, which contain softeners. In many cases, the shells of the capsules get so brittle that the enclosures burst and the fillings contained in them are set free. Sometimes it even happens that such brittle capsules are destroyed already during transportation as bulk material because they cannot resist the mechanical stresses encountered.
In other cases, the affinity of polyethylene glycols to the shells may induce the polyethylene glycols to diffuse during storage from the fillings into the gelatin enclosure. Since the polyethylene glycols act as softeners, the capsules get very soft. They stick together and deform, and when sealed into plastic films they can no longer be pressed out without damage to the capsules. In many cases, the polyethylene glycol diffuses through the enclosure so that the surface of the shell gets smeary. Capsules in this condition must be regarded as bad.
German Patent Specification No. 22 09 526 describes soft gelatin capsules, the shell of which contains glycerol as a softener and the fillings of which contain polyethylene glycols with a mean molecular weight of between 300 to 600, together with a small proportion of glycerol and water. The polyethylene glycol for the capsules actually described in this Patent Specification consists exclusively of polyethylene glycol 400. German Patent Specification No. 22 09 526 states that optimum results are achieved with capsules of the described composition. However, if one tries to transfer the compositions specified in the said German Patent Specification No. 22 09 526 to capsules containing other active substances or of other capsule sizes, failures will be encountered, again and again, insofar as during storage, the capsules will change in hardness and flexibility, get brittle or soft, or polyethylene glycol will diffuse through the shell. And even when producing capsules in accordance with German Patent Specification No. 22 09 526, using the active substance specified therein, it will be found that the hardness of the capsules will change heavily during storage. So, there is still a need for soft capsules containing polyethylene glycol which can be manufactured in a reproducible manner as stable and durable medicines.